Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?

Abstract

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities.

Key points

  • Episodic memory has limited utility as a diagnostic and outcome measure for preclinical Alzheimer disease (AD).

  • Spatial navigation deficits have the potential to detect underlying pathophysiology in preclinical AD.

  • The brain areas affected earliest by AD pathophysiology are key nodes in the spatial navigation network.

  • Genetically at-risk individuals show altered spatial navigation patterns before any episodic memory symptom onset.

  • Spatial navigation is emerging as a potential cost-effective cognitive biomarker to detect AD in the preclinical stages, which has important implications for future diagnostics and treatment approaches.

  • Future spatial navigation benchmarks and standardization of spatial navigation tests are needed to realize this goal.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Egocentric and allocentric spatial coding.
Fig. 2: Anatomical illustration of AD-related neuropathological changes.
Fig. 3: The progressive pathophysiological changes that underlie navigational impairment in AD.

References

  1. 1.

    Blennow, K., de Leon, M. J. & Zetterberg, H. Alzheimer’s disease. Lancet 368, 387–403 (2006).

    PubMed  CAS  Google Scholar 

  2. 2.

    Alzheimer’s Association. 2015 Alzheimer’s disease facts and figures. Alzheimers Dement. 11, 459–509 (2015).

    Google Scholar 

  3. 3.

    Habchi, J. et al. An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimers disease. Sci. Adv. 2, e1501244–e1501244 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  4. 4.

    Sevigny, J. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Yang, T. et al. Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment. PLoS ONE 3, e3604 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Vauzour, D. et al. Nutrition for the ageing brain: towards evidence for an optimal diet. Ageing Res. Rev. 35, 222–240 (2017).

    PubMed  Article  Google Scholar 

  7. 7.

    Dubois, B. et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 13, 614–629 (2014).

    PubMed  Article  Google Scholar 

  8. 8.

    Rajah, M. N. et al. Family history and APOE4 risk for Alzheimer’s disease impact the neural correlates of episodic memory by early midlife. NeuroImage Clin. 14, 760–774 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. 9.

    Bellassen, V., Igloi, K., de Souza, L. C., Dubois, B. & Rondi-Reig, L. Temporal order memory assessed during spatiotemporal navigation as a behavioral cognitive marker for differential alzheimer’s disease diagnosis. J. Neurosci. 32, 1942–1952 (2012).

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Birrer, R. B. & Vemuri, S. P. Depression in later life: a diagnostic and therapeutic challenge. Am. Fam. Physician 69, 2375–2382 (2004).

    PubMed  Google Scholar 

  11. 11.

    Bronnick, K., Emre, M., Tekin, S., Haugen, S. B. & Aarsland, D. Cognitive correlates of visual hallucinations in dementia associated with Parkinson’s disease. Mov. Disord. 26, 824–829 (2011).

    PubMed  Article  Google Scholar 

  12. 12.

    Pennington, C., Hodges, J. R. & Hornberger, M. Neural correlates of episodic memory in behavioral variant frontotemporal dementia. J. Alzheimers Dis. 24, 261–268 (2011).

    PubMed  Article  Google Scholar 

  13. 13.

    Flanagan, E. C. et al. False recognition in behavioral variant frontotemporal dementia and Alzheimer’s disease-disinhibition or amnesia? Front. Aging Neurosci. 8, 1–11 (2016).

    Article  Google Scholar 

  14. 14.

    Tu, S. et al. Lost in spatial translation - a novel tool to objectively assess spatial disorientation in Alzheimer’s disease and frontotemporal dementia. Cortex 67, 83–94 (2015).

    PubMed  Article  Google Scholar 

  15. 15.

    Yew, B., Alladi, S., Shailaja, M., Hodges, J. R. & Hornberger, M. Lost and forgotten? Orientation versus memory in Alzheimer’s disease and frontotemporal dementia. J. Alzheimers Dis. 33, 473–481 (2013).

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Fu, H. et al. Tau pathology induces excitatory neuron loss, grid cell dysfunction, and spatial memory deficits reminiscent of early Alzheimer’s Disease. Neuron 93, 533–541 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Serino, S., Morganti, F., Di Stefano, F. & Riva, G. Detecting early egocentric and allocentric impairments deficits in Alzheimer’s disease: an experimental study with virtual reality. Front. Aging Neurosci. 7, 1–10 (2015).

    Article  Google Scholar 

  18. 18.

    Lithfous, S., Dufour, A. & Després, O. Spatial navigation in normal aging and the prodromal stage of Alzheimer’s disease: insights from imaging and behavioral studies. Ageing Res. Rev. 12, 201–213 (2013).

    PubMed  Article  Google Scholar 

  19. 19.

    Templer, V. & Hampton, R. Episodic memory in nonhuman animals. Curr. Biol. 23, 801–806 (2013).

    Article  CAS  Google Scholar 

  20. 20.

    Allison, S. L., Fagan, A. M., Morris, J. C. & Head, D. Spatial navigation in preclinical Alzheimer’s disease. J. Alzheimers Dis. 52, 77–90 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Kunz, L. et al. Reduced grid-cell-like representations in adults at genetic risk for Alzheimer’s disease. Science 350, 430–433 (2015).

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Jack Jr, C. R. et al. Introduction to revised criteria for the diagnosis of Alzheimer’s disease: National Institute on Aging and the Alzheimer Association Workgroups. Alzheimers Dement. 7, 257–262 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Medina, M. & Avila, J. New perspectives on the role of tau in Alzheimer’s disease. Implications for therapy. Biochem. Pharmacol. 88, 540–547 (2014).

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Nelson, P. T. et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J. Neuropathol. Exp. Neurol. 71, 362–381 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Knopman, D. S. et al. Neuropathology of cognitively normal elderly. J. Neuropathol. Exp. Neurol. 62, 1087–1095 (2003).

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Chételat, G. et al. Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer’s disease. NeuroImage Clin. 2, 356–365 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Morris, G. P., Clark, I. A. & Vissel, B. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s Disease. Acta Neuropathol. Commun. 2, 1–21 (2014).

    Article  Google Scholar 

  28. 28.

    Galton, C. J., Patterson, K., Xuereb, J. H. & Hodges, J. R. Atypical and typical presentations of Alzheimer’s disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases. Brain 123, 484–498 (2000).

    PubMed  Article  Google Scholar 

  29. 29.

    Braak, H. & Del Tredici, K. The preclinical phase of the pathological process underlying sporadic Alzheimer’s disease. Brain 138, 2814–2833 (2015).

    PubMed  Article  Google Scholar 

  30. 30.

    Hartshorne, J. K. & Germine, L. T. When does cognitive functioning peak? The asynchron. rise fall different cognitive abilities across life span. Psychol. Sci. 26, 433–443 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Park, H. L., O’Connell, J. E. & Thomson, R. G. A systematic review of cognitive decline in the general elderly population. Int. J. Geriatr. Psychiatry 18, 1121–1134 (2003).

    PubMed  Article  Google Scholar 

  32. 32.

    Brayne, C. et al. Estimating the true extent of cognitive decline in the old old. J. Am. Geriatr. Soc. 47, 1283–1288 (1999).

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Brailean, A. et al. Cohort differences in cognitive aging in the longitudinal aging study Amsterdam. J. Gerontol. B Psychol. Sci. Soc. Sci. https://doi.org/10.1093/geronb/gbw129 (2016).

  34. 34.

    Bertoux, M. et al. Two distinct amnesic profiles in behavioral variant frontotemporal dementia. Biol. Psychiatry 75, 582–588 (2014).

    PubMed  Article  Google Scholar 

  35. 35.

    Hornberger, M., Piguet, O., Graham, A. J., Nestor, P. J. & Hodges, J. R. How preserved is episodic memory in behavioral variant frontotemporal dementia? Neurology 74, 472–479 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. 36.

    Hornberger, M. & Piguet, O. Episodic memory in frontotemporal dementia: a critical review. Brain 135, 678–692 (2012).

    PubMed  Article  Google Scholar 

  37. 37.

    Wong, S., Flanagan, E., Savage, G., Hodges, J. R. & Hornberger, M. Contrasting prefrontal cortex contributions to episodic memory dysfunction in behavioural variant frontotemporal dementia and alzheimer’s disease. PLoS ONE 9, e87778 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Cerman, J. et al. Subjective spatial navigation complaints - a frequent symptom reported by patients with subjective cognitive decline, mild cognitive impairment and Alzheimer’s disease. Curr. Alzheimer Res. 15, 219–228 (2017).

    Article  CAS  Google Scholar 

  39. 39.

    Tu, S., Spiers, H. J., Hodges, J. R., Piguet, O. & Hornberger, M. Egocentric versus allocentric spatial memory in behavioral variant frontotemporal dementia and Alzheimer’s disease. J. Alzheimers Dis. 59, 883–892 (2017).

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Killian, N. J. & Buffalo, E. A. Grid cells map the visual world. Nat. Neurosci. 21, 161–162 (2018).

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Hafting, T., Fyhn, M., Molden, S., Moser, M.-B. & Moser, E. I. Microstructure of a spatial map in the entorhinal cortex. Nature 436, 801–806 (2005).

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    McNaughton, B. L., Battaglia, F. P., Jensen, O., Moser, E. I. & Moser, M. B. Path integration and the neural basis of the ‘cognitive map’. Nat. Rev. Neurosci. 7, 663–678 (2006).

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Fuhs, M. C. & Touretzky, D. S. A. Spin glass model of path integration in rat medial entorhinal cortex. J. Neurosci. 26, 4266–4276 (2006).

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Boccia, M., Nemmi, F. & Guariglia, C. Neuropsychology of environmental navigation in humans: review and meta-analysis of fMRI studies in healthy participants. Neuropsychol. Rev. 24, 236–251 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Wolbers, T., Weiller, C. & Büchel, C. Neural foundations of emerging route knowledge in complex spatial environments. Brain Res. Cogn. Brain Res. 21, 401–411 (2004).

    PubMed  Article  Google Scholar 

  46. 46.

    Hartley, T., Maguire, E. A., Spiers, H. J. & Burgess, N. The well-worn route and the path less traveled: distinct neural bases of route following and wayfinding in humans. Neuron 37, 877–888 (2003).

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    O’Keefe, John & Nadel, L. The Hippocampus as a Cognitive Map (Oxford University Press, Oxford, 1978).

    Google Scholar 

  48. 48.

    Loomis, J. M., Golledge, R. G. & Klatzky, R. L. Navigation system for the blind: auditory display modes and guidance. Presence Teleoperators virtual Environments 7, 193–203 (1998).

    Article  Google Scholar 

  49. 49.

    Loomis, J. M. et al. Nonvisual navigation by blind and sighted: assessment of path integration ability. J. Exp. Psychol. Gen. 122, 73–91 (1993).

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Spiers, H. J. & Barry, C. Neural systems supporting navigation. Curr. Opin. Behav. Sci. 1, 47–55 (2015).

    Article  Google Scholar 

  51. 51.

    Byrne, P., Becker, S. & Burgess, N. Remembering the past and imagining the future: a neural model of spatial memory and imagery. Psychol. Rev. 114, 340–375 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Chiu, T. C. et al. Alpha modulation in parietal and retrosplenial cortex correlates with navigation performance. Psychophysiology 49, 43–55 (2012).

    PubMed  Article  Google Scholar 

  53. 53.

    Gaffan, D. Scene-specific memory for objects: a model of episodic memory impairment in monkeys with fornix transection. J. Cogn. Neurosci. 6, 305–320 (1994).

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    King, J. A., Trinkler, I., Hartley, T., Vargha-Khadem, F. & Burgess, N. The hippocampal role in spatial memory and the familiarity—recollection distinction: a case study. Neuropsychology 18, 405–417 (2004).

    PubMed  Article  Google Scholar 

  55. 55.

    Feigenbaum, J. D. & Morris, R. G. Allocentric versus egocentric spatial memory after unilateral temporal lobectomy in humans. Neuropsychology 18, 462–472 (2004).

    PubMed  Article  Google Scholar 

  56. 56.

    Parslow, D. M. et al. Allocentric spatial memory activation of the hippocampal formation measured with fMRI. Neuropsychology 18, 450–461 (2004).

    PubMed  Article  Google Scholar 

  57. 57.

    Ekstrom, A. D. et al. Cellular networks underlying human spatial navigation. Nature 425, 184–188 (2003).

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Maguire, E. a et al. Knowing where and getting there: a human navigation network. Science 280, 921–924 (1998).

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Auger, S. D., Mullally, S. L. & Maguire, E. A. Retrosplenial cortex codes for permanent landmarks. PLoS ONE 7, e43620 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  60. 60.

    Auger, S. D. & Maguire, E. A. Assessing the mechanism of response in the retrosplenial cortex of good and poor navigators. Cortex 49, 2904–2913 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Moffat, S. D., Kennedy, K. M., Rodrigue, K. M. & Raz, N. Extrahippocampal contributions to age differences in human spatial navigation. Cereb. Cortex 17, 1274–1282 (2007).

    PubMed  Article  Google Scholar 

  62. 62.

    Aggleton, J. P., Pralus, A., Nelson, A. J. D. & Hornberger, M. Thalamic pathology and memory loss in early Alzheimer’s disease: moving the focus from the medial temporal lobe to Papez circuit. Brain 139, 1877–1890 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Aggleton, J. P. & Nelson, A. J. D. Why do lesions in the rodent anterior thalamic nuclei cause such severe spatial deficits? Neurosci. Biobehav. Rev. 54, 131–144 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Doeller, C. C. F., Barry, C. & Burgess, N. Evidence for grid cells in a human memory network. Nature 463, 657–661 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. 65.

    Burgess, N., Barry, C. & O’Keefe, J. An oscillatory interference model of grid cell firing. Hippocampus 17, 801–812 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Taube, J. S., Muller, R. U. & Ranck, J. B. Head-direction cells recorded from the postsubiculum in freely moving rats. II. Effects of environmental manipulations.J. Neurosci. 70, 436–447 (1990).

    Article  Google Scholar 

  67. 67.

    Muller, R. U., Ranck Jr., J. B. & Taube, J. S. Head direction cells: properties and functional significance. Curr. Opin. Neurobiol. 6, 196–206 (1996).

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Shine, J. P., Valdes-Herrera, J. P., Hegarty, M. & Wolbers, T. The human retrosplenial cortex and thalamus code head direction in a global reference frame. J. Neurosci. 36, 6371–6381 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. 69.

    Lever, C., Burton, S., Jeewajee, A., Keefe, J. O. & Burgess, N. Europe PMC funders group boundary vector cells in the subiculum of the hippocampal formation. J. Neurosci. 29, 9771–9777 (2010).

    Article  CAS  Google Scholar 

  70. 70.

    Mahmood, O., Adamo, D., Briceno, E. & Moffat, S. D. Age differences in visual path integration. Behav. Brain Res. 205, 88–95 (2009).

    PubMed  Article  Google Scholar 

  71. 71.

    Alexander, A. S. & Nitz, D. A. Retrosplenial cortex maps the conjunction of internal and external spaces. Nat. Neurosci. 18, 1143–1151 (2015).

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Czajkowski, R. et al. Encoding and storage of spatial information in the retrosplenial cortex. Proc. Natl Acad. Sci. USA 111, 8661–8666 (2014).

    PubMed  Article  CAS  Google Scholar 

  73. 73.

    Bird, C. M., Keidel, J. L., Ing, L. P., Horner, A. J. & Burgess, N. Consolidation of complex events via reinstatement in posterior cingulate cortex. J. Neurosci. 35, 14426–14434 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Dhindsa, K. et al. Examining the role of the temporo-parietal network in memory, imagery, and viewpoint transformations. Front. Hum. Neurosci. 8, 1–13 (2014).

    Article  Google Scholar 

  75. 75.

    Vass, L. K. & Epstein, R. A. Abstract representations of location and facing direction in the human brain. J. Neurosci. 33, 6133–6142 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Clark, B. J., Brown, J. E. & Taube, J. S. Head direction cell activity in the anterodorsal thalamus requires intact supragenual nuclei. J. Neurophysiol. 108, 2767–2784 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Knight, R. & Hayman, R. Allocentric directional processing in the rodent and human retrosplenial cortex. Front. Hum. Neurosci. 8, 1–5 (2014).

    Article  Google Scholar 

  78. 78.

    Chersi, F. & Pezzulo, G. Using hippocampal-striatal loops for spatial navigation and goal-directed decision-making. Cogn. Process. 13, 125–129 (2012).

    Article  Google Scholar 

  79. 79.

    Sheynikhovich, D., Chavarriaga, R., Strösslin, T., Arleo, A. & Gerstner, W. Is there a geometric module for spatial orientation? Insights from a rodent navigation model. Psychol. Rev. 116, 540–566 (2009).

    PubMed  Article  Google Scholar 

  80. 80.

    Elduayen, C. & Save, E. The retrosplenial cortex is necessary for path integration in the dark. Behav. Brain Res. 272, 303–307 (2014).

    PubMed  Article  Google Scholar 

  81. 81.

    Mullally, S. L. & Maguire, E. A. A. New role for the parahippocampal cortex in representing space. J. Neurosci. 31, 7441–7449 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. 82.

    Iaria, G., Palermo, L., Committeri, G. & Barton, J. J. S. Age differences in the formation and use of cognitive maps. Behav. Brain Res. 196, 187–191 (2009).

    PubMed  Article  Google Scholar 

  83. 83.

    Moffat, S. D. et al. Effects of age on virtual environment place navigation and allocentric cognitive mapping. Behav. Neurosci. 116, 851–859 (2002).

    PubMed  Article  Google Scholar 

  84. 84.

    Gazova, I. et al. Spatial navigation in young versus older adults. Front. Aging Neurosci. 5, 1–8 (2013).

    Article  Google Scholar 

  85. 85.

    Moffat, S. D. Aging and spatial navigation: what do we know and where do we go? Neuropsychol. Rev. 19, 478–489 (2009).

    PubMed  Article  Google Scholar 

  86. 86.

    Heo, S. et al. Resting hippocampal blood flow, spatial memory and aging. Brain Res. 1315, 119–127 (2010).

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Bach, M. E. et al. Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc. Natl Acad. Sci. USA 96, 5280–5285 (1999).

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Driscoll, I. et al. Longitudinal pattern of regional brain volume change differentiates normal aging from MCI. Neurology 72, 1906–1913 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 89.

    Lalonde-Parsi, M.-J. & Lamontagne, A. Perception of self-motion and regulation of walking speed in young-old adults. Motor Control 19, 191–206 (2015).

    PubMed  Article  Google Scholar 

  90. 90.

    Holden, H. M. & Gilbert, P. E. Less efficient pattern separation may contribute to age-related spatial memory deficits. Front. Aging Neurosci. 4, 1–6 (2012).

    Article  Google Scholar 

  91. 91.

    Lester, A. W., Moffat, S. D., Wiener, J. M., Barnes, C. A. & Wolbers, T. The aging navigational system. Neuron 95, 1019–1035 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  92. 92.

    Carpenter, H. E., Kelly, K. B., Bizon, J. L. & Frazier, C. J. Age-related changes in tonic activation of presynaptic versus extrasynaptic γ-amniobutyric acid type B receptors in rat medial prefrontal cortex. Neurobiol. Aging 45, 88–97 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  93. 93.

    Rodgers, M. K., Sindone, J. A. & Moffat, S. D. Effects of age on navigation strategy. Neurobiol. Aging 33, 202.e15–202.e22 (2012).

    Article  Google Scholar 

  94. 94.

    Zheng Bian & George Andersen, J. Aging and the perception of egocentric distance. Psychol. Aging 28, 813–825 (2013).

    PubMed  Article  Google Scholar 

  95. 95.

    Norman, J. F., Adkins, O. C., Norman, H. F., Cox, A. G. & Rogers, C. E. Aging and the visual perception of exocentric distance. Vision Res. 109, 52–58 (2015).

    PubMed  Article  Google Scholar 

  96. 96.

    Vandenberg, S. G. & Kuse, A. R. Mental rotations, a group test of three-dimensional spatial visualization. Percept. Mot. Skills 47, 599–604 (1978).

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Money, J. et al. A standardized road-map test of direction sense; Manual (Johns Hopkins Press, Baltimore, MD, 1965).

    Google Scholar 

  98. 98.

    Mitolo, M. et al. Relationship between spatial ability, visuospatial working memory and self-assessed spatial orientation ability: a study in older adults. Cogn. Process. 16, 165–176 (2015).

    PubMed  Article  Google Scholar 

  99. 99.

    Schinazi, V. R., Nardi, D., Newcombe, N. S., Shipley, T. F. & Epstein, R. A. Hippocampal size predicts rapid learning of a cognitive map in humans. Hippocampus 23, 515–528 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Mapstone, M., Steffenella, T. M. & Duffy, C. J. A visuospatial variant of mild cognitive impairment: getting lost between aging and AD. Neurology 60, 802–808 (2003).

    PubMed  Article  Google Scholar 

  101. 101.

    Cushman, L. A. & Duffy, C. J. Virtual reality identifies navigational defects in Alzheimer disease and cognitive aging. Nat. Clin. Pract. Neurol. 4, 638–639 (2008).

    Google Scholar 

  102. 102.

    Cogné, M. et al. The contribution of virtual reality to the diagnosis of spatial navigation disorders and to the study of the role of navigational aids: a systematic literature review. Ann. Phys. Rehabil. Med. 60, 164–176 (2017).

    PubMed  Article  Google Scholar 

  103. 103.

    Pengas, G. et al. The relationship of topographical memory performance to regional neurodegeneration in Alzheimer’s disease. Front. Aging Neurosci. 4, 1–10 (2012).

    Article  Google Scholar 

  104. 104.

    Jheng, S. S. & Pai, M. C. Cognitive map in patients with mild Alzheimer’s disease: a computer-generated arena study. Behav. Brain Res. 200, 42–47 (2009).

    PubMed  Article  Google Scholar 

  105. 105.

    Serino, S. & Riva, G. Getting lost in Alzheimer’s disease: a break in the mental frame syncing. Med. Hypotheses 80, 416–421 (2013).

    PubMed  Article  Google Scholar 

  106. 106.

    Irish, M. et al. Scene construction impairments in Alzheimer’s disease - a unique role for the posterior cingulate cortex. Cortex 73, 10–23 (2015).

    PubMed  Article  Google Scholar 

  107. 107.

    Padurariu, M., Ciobica, A., Mavroudis, I., Fotiou, D. & Baloyannis, S. Hippocampal neuronal loss in the CA1 and CA3 areas of Alzheimer’s disease patients. Psychiatr. Danub. 24, 152–158 (2012).

    PubMed  Google Scholar 

  108. 108.

    Weniger, G., Ruhleder, M., Lange, C., Wolf, S. & Irle, E. Egocentric and allocentric memory as assessed by virtual reality in individuals with amnestic mild cognitive impairment. Neuropsychologia 49, 518–527 (2011).

    PubMed  Article  Google Scholar 

  109. 109.

    Tan, R. H., Wong, S., Hodges, J. R., Halliday, G. M. & Hornberger, M. Retrosplenial cortex (BA 29) volumes in behavioral variant frontotemporal dementia and alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 35, 177–182 (2013).

    PubMed  Article  Google Scholar 

  110. 110.

    Morganti, F., Stefanini, S. & Riva, G. From allo- to egocentric spatial ability in early Alzheimer’s disease: a study with virtual reality spatial tasks. Cogn. Neurosci. 4, 171–180 (2013).

    PubMed  Article  Google Scholar 

  111. 111.

    Hort, J. et al. Spatial navigation deficit in amnestic mild cognitive impairment. Proc. Natl Acad. Sci. USA 104, 4042–4047 (2007).

    PubMed  Article  CAS  Google Scholar 

  112. 112.

    Jack, C. R. et al. Suspected non-Alzheimer disease pathophysiology—concept and controversy. Nat. Rev. Neurol. 12, 117–124 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    DeIpolyi, A. R., Rankin, K. P., Mucke, L., Miller, B. L. & Gorno-Tempini, M. L. Spatial cognition and the human navigation network in AD and MCI. Neurology 69, 986–997 (2007).

    PubMed  Article  CAS  Google Scholar 

  114. 114.

    Dubois, B. & Albert, M. L. Amnestic MCI or prodromal Alzheimer’s disease? Lancet Neurol. 3, 246–248 (2004).

    PubMed  Article  Google Scholar 

  115. 115.

    Laczó, J., Andel, R., Vyhnalek, M. & Vlcek, K. APOE and spatial navigation in amnestic MCI: results from a computer-based test. Neuropsychology 28, 676–684 (2014).

    PubMed  Article  Google Scholar 

  116. 116.

    Julkunen, V. et al. Cortical thickness analysis to detect progressive mild cognitive impairment: a reference to Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 28, 404–412 (2009).

    PubMed  Article  Google Scholar 

  117. 117.

    Mokrisova, I. et al. Real-space path integration is impaired in Alzheimer’s disease and mild cognitive impairment. Behav. Brain Res. 307, 150–158 (2016).

    PubMed  Article  CAS  Google Scholar 

  118. 118.

    Laczó, J. et al. Spatial navigation testing discriminates two types of amnestic mild cognitive impairment. Behav. Brain Res. 202, 252–259 (2009).

    PubMed  Article  Google Scholar 

  119. 119.

    Genin, E. et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol. Psychiatry 16, 903–907 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  120. 120.

    Scahill, R. I., Schott, J. M., Stevens, J. M., Rossor, M. N. & Fox, N. C. Mapping the evolution of regional atrophy in Alzheimer’s disease: unbiased analysis of fluid-registered serial MRI. Proc. Natl Acad. Sci. USA 99, 4703–4707 (2002).

    PubMed  Article  CAS  Google Scholar 

  121. 121.

    Pengas, G., Hodges, J. R., Watson, P. & Nestor, P. J. Focal posterior cingulate atrophy in incipient Alzheimer’s disease. Neurobiol. Aging 31, 25–33 (2010).

    PubMed  Article  Google Scholar 

  122. 122.

    Fennema-Notestine, C. et al. Structural MRI biomarkers for preclinical and mild Alzheimer’s disease. Hum. Brain Mapp. 30, 3238–3253 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Hämäläinen, A. et al. Voxel-based morphometry to detect brain atrophy in progressive mild cognitive impairment. Neuroimage 37, 1122–1131 (2007).

    PubMed  Article  Google Scholar 

  124. 124.

    Whitwell, J. L. et al. MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study. Neurology 71, 743–749 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. 125.

    van Groen, T. & Michael Wyss, J. Connections of the retrosplenial granular a cortex in the rat. J. Comp. Neurol. 300, 593–606 (1990).

    PubMed  Article  Google Scholar 

  126. 126.

    Tan, C. C., Yu, J. T. & Tan, L. Biomarkers for preclinical alzheimer’s disease. J. Alzheimers Dis. 42, 1051–1069 (2014).

    PubMed  Article  CAS  Google Scholar 

  127. 127.

    Patel, K. T. et al. Default mode network activity and white matter integrity in healthy middle-aged ApoE4 carriers. Brain Imaging Behav. 7, 60–67 (2013).

    PubMed  Article  Google Scholar 

  128. 128.

    Pihlajamaki, M. et al. Evidence of altered posteromedial cortical fMRI activity in subjects at risk for Alzheimer disease. Alzheimer Dis. Assoc. Disord. 24, 28–36 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Skoog, I. et al. Cerebrospinal fluid beta-amyloid 42 is reduced before the onset of sporadic dementia: a population-based study in 85-year-olds. Dement. Geriatr. Cogn. Disord. 15, 169–176 (2003).

    PubMed  Article  CAS  Google Scholar 

  130. 130.

    Villemagne, V. L., Fodero-Tavoletti, M. T., Masters, C. L. & Rowe, C. C. Tau imaging: early progress and future directions. Lancet Neurol. 14, 114–124 (2015).

    PubMed  Article  Google Scholar 

  131. 131.

    Johnson, K. A. et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann. Neurol. 79, 110–119 (2016).

    PubMed  Article  Google Scholar 

  132. 132.

    Weston, P. S. J. et al. Presymptomatic cortical thinning in familial Alzheimer disease: a longitudinal MRI study. Neurology 87, 2050–2057 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Yasen, A. L., Raber, J., Miller, J. K. & Piper, B. J. Sex, but not apolipoprotein E polymorphism, differences in spatial performance in young adults. Arch. Sex. Behav. 44, 2219–2226 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Bunce, D. et al. APOE genotype and cognitive change in young, middle- aged, and older adults living in the community. J. Gerontol. A Biol. Sci. Med. Sci. 69, 379–386 (2014).

    PubMed  Article  CAS  Google Scholar 

  135. 135.

    Salvato, G., Patai, E. Z., McCloud, T. & Nobre, A. C. Apolipoprotein ε4 breaks the association between declarative long-term memory and memory-based orienting of spatial attention in middle-aged individuals. Cortex 82, 206–216 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Greenwood, P. M., Lambert, C., Sunderland, T. & Parasuraman, R. Effects of apolipoprotein E genotype on spatial attention, working memory, and their interaction in healthy, middle - aged adults: results from the National Institute of Mental Health ’s BIOCARD Study. Neuropsychology 2, 199–211 (2015).

    Google Scholar 

  137. 137.

    Parasuraman, R., Greenwood, P. M. & Sunderland, T. The apolipoprotein E gene, attention, and brain function. Neuropsychology 16, 254–274 (2002).

    PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Evans, S. et al. Cognitive and neural signatures of the APOE E4 allele in mid-aged adults. Neurobiol. Aging 35, 1615–1623 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  139. 139.

    Berteau-Pavy, F., Park, B. & Raber, J. Effects of sex and APOE epsilon 4 on object recognition and spatial navigation in the elderly. Neuroscience 147, 6–17 (2007).

    PubMed  Article  CAS  Google Scholar 

  140. 140.

    Bott, J.-B. et al. APOE sensitive cholinergic sprouting compensates for hippocampal dysfunctions due to reduced entorhinal input. J. Neurosci. 36, 10472–10486 (2016).

    PubMed  Article  CAS  Google Scholar 

  141. 141.

    Risacher, S. L. et al. APOE effect on Alzheimer’s disease biomarkers in older adults with significant memory concern. Alzheimers Dement. 11, 1417–1429 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Amariglio, R. E. et al. Specific SMC in older persons may indicate poor cognitive function. J. Am. Geriatr. Soc. 59, 1612–1617 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Amariglio, R. E. et al. Subjective cognitive complaints and amyloid burden in cognitively normal older individuals. Neuropsychologia 50, 2880–2886 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Hort, J. et al. Effect of donepezil in alzheimer disease can be measured by a computerized human analog of the morris water maze. Neurodegener. Dis. 13, 192–196 (2014).

    PubMed  Article  CAS  Google Scholar 

  145. 145.

    Laczó, J. et al. Scopolamine disrupts place navigation in rats and humans: a translational validation of the hidden goal task in the morris water maze and a real maze for humans. Psychopharmacol. 234, 535–547 (2016).

    Article  CAS  Google Scholar 

  146. 146.

    Coutrot, A. et al. Global determinants of navigation ability. Preprint at https://www.biorxiv.org/content/early/2017/09/14/188870.1 (2018).

  147. 147.

    Coutrot, A. et al. Virtual navigation tested on a mobile app (Sea Hero Quest) is predictive of real-world navigation performance: preliminary data. Preprint at https://www.biorxiv.org/content/early/2018/04/22/305433 (2018).

  148. 148.

    Coughlan, G. et al. Impact of sex and APOE status on spatial navigation in pre- symptomatic Alzheimer’s disease. Preprint at https://www.biorxiv.org/content/early/2018/03/23/287722 (2018).

  149. 149.

    Vorhees, C. V. & Williams, M. T. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 1, 848–858 (2006).

    PubMed  PubMed Central  Article  Google Scholar 

  150. 150.

    Vann, S. D., Aggleton, J. P. & Maguire, E. A. What does the retrosplenial cortex do? Nat. Rev. Neurosci. 10, 792–802 (2009).

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

M.H. and G.C. contributed to all aspects of the manuscript. J.L. and J.H. contributed to reviewing and editing the manuscript before submission. A.-M.M. contributed to writing of the manuscript.

Corresponding author

Correspondence to Michael Hornberger.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Reviewer information

Nature Reviews Neurology thanks T. Brandt, K. Possin and T. Wolbers for their contribution to the peer review of this work.

Related link

Sea Hero Quest: www.seaheroquest.com

Glossary

Episodic memory

One’s memory of events represented by aspects of the past not present in other memories, such as the time, place or social context.

Mild cognitive impairment

(MCI). Prodromal or intermediate stage between the expected cognitive decline of normal ageing and the more serious decline of dementia.

Egocentric navigation strategies

Egocentric self-centred navigation frames encode spatial information from the viewpoint of the navigator.

Allocentric navigation strategies

Allocentric strategies are based on the navigator’s perception of landmark positions relative to other landmarks.

Morris water maze

A test of spatial learning examining rodent ability to navigate from different starting locations around an open swimming arena to locate a submerged escape platform using only distal cues. For more information, see elsewhere149.

Significant memory concerns

(SMCs). Self-experienced persistent declines in cognitive abilities in comparison with a prior normal status; occur in the absence of objective impairment on standardized neuropsychological tests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Coughlan, G., Laczó, J., Hort, J. et al. Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?. Nat Rev Neurol 14, 496–506 (2018). https://doi.org/10.1038/s41582-018-0031-x

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing